Uncertainty and stress: Why it causes diseases and how it is mastered by the brain

“From a theoretical perspective, the difference between attainable states and goal states can be formalized by the so-called ‘Kullback Leibler (KL) divergence’ (Kullback and Leibler, 1951).”

“How exactly these procedures are executed is one of the most fascinating questions in neuroscience (Friston, 2010).”

“The brain’s architecture is hierarchically organized (Felleman and Van, 1991).”

“All of these long-lasting effects of persistently activated stress reactions are called ‘allostatic load’ (McEwen, 1998).”

“It has been shown that both perceptual inference and learning can be described as a minimization of free energy or the suppression of prediction errors (Friston, 2005; Rao and Ballard, 1999).”

“In the short run, increased vigilance or anxiety in a hostile environment may be adaptive; however, when the danger passes and the behavioral state and the changes in neural circuitry become chronic, which get ‘stuck’, such maladaptation may require an external intervention to get it ‘unstuck’, as is the case for chro…”

“It has been shown that both perceptual inference and learning can be described as a minimization of free energy or the suppression of prediction errors (Friston, 2005; Rao and Ballard, 1999).”

“In this mode, LC projections to cortical areas lead to enhancement of only the few parts of the cortex involved in a specific task (Aston-Jones and Cohen, 2005; Berridge and Waterhouse, 2003).”

“, 1983) – particularly at branching sites of the blood vessel system (Malek et al., 1999).”

“when the individuals live in poverty, in warafflicted areas, are long-term unemployed or victims of discrimination (Kubera et al., 2016; Ludwig et al., 2012; Puhl and Heuer, 2009).”

“When serious damage manifests, the effects are referred to as ‘allostatic overload’ (McEwen and Wingfield, 2003).”

“demonstrated that neurons take up energy ‘on demand’ (Magistretti et al., 1999; Pellerin and Magistretti, 1994).”

“Thus, a setpoint is generated that depends primarily on the functioning of the MR in coordination with GR (de Kloet et al., 1998; Peters et al., 2007a).”

“In this mode, LC projections to cortical areas lead to enhancement of only the few parts of the cortex involved in a specific task (Aston-Jones and Cohen, 2005; Berridge and Waterhouse, 2003).”

“, 2000; Ramaswamy and Markram, 2015; Thomson and Lamy, 2007) and neurocomputational analyses (Bastos et al., 2012; Haeusler and Maass, 2007; Shipp, 2016; Shipp et al., 2013), we propose the following assignment of empirical prior beliefs, the likelihood, the sensory data, and the prediction errors to their anatomical…”

“…stress-related responses are broadcast by the ACC to the anterior insular and onto autonomic centers to elicit autonomic reflexes (Barrett and Simmons, 2015; Behrens et al., 2007; Feinstein et al., 2006; Karlsson et al., 2012; Liljeholm et al., 2013; Paulus et al., 2002; Sarinopoulos et al., 2010).”

“The ‘states that agents believe they should occupy’ are represented in regions like the ventromedial prefrontal cortex prefrontal cortex (vmPFC) and the orbitofrontal cortex (OFC) (Barron et al., 2015; Bechara et al., 2000; Gottfried et al., 2003; O'Doherty et al., 2003; Roesch and Olson, 2004).”

“In short, there is an optimum balance between approach and avoidance behavior that rests upon environmental volatility and, more importantly, the ability of an agent to estimate volatility and use it to minimize long-term uncertainty (Friston, 2009).”

“…predictions of stress-related responses are broadcast by the ACC to the anterior insular and onto autonomic centers to elicit autonomic reflexes (Barrett and Simmons, 2015; Behrens et al., 2007; Feinstein et al., 2006; Karlsson et al., 2012; Liljeholm et al., 2013; Paulus et al., 2002;…”

“Crucially, enhanced information transmission at synapses is itself particularly expensive in terms of energy (Harris et al., 2012).”

“A successful update would require a reorganization of the brain architecture and neuronal circuits that includes synaptic plasticity (LTP) and structural plasticity (spine remodeling; rebuilding of the dendritic trees) (McEwen et al., 2016).”

“‘Adaptive vascular remodeling’ describes processes in the vasculature that ameliorate such turbulences (Chatzizisis et al., 2007).”

“updated by bottom-up prediction errors (Friston et al., 2006).”

“A few years ago, it was shown that if the input from an excitatory neuron A and the input from an inhibitory neuron B are correlated, then the fluctuations of the postsynaptic neuron decrease (Salinas and Sejnowski, 2001).”

“But neurons can also can sum up their inputs to elicit an action potential (Konig et al., 1996; Shadlen and Newsome, 1994).”

“From the physical point of view, the following applies: Obtaining any information costs energy, erasing information produces energy (Berut et al., 2012; Brillouin, 1953; Toyabe et al., 2014; Tribus and McIrvine, 1972).”

“In agreement with neuroanatomical studies (Feldmeyer et al., 2005; Harris and Shepherd, 2015; Lubke et al., 2000; Ramaswamy and Markram, 2015; Thomson and Lamy, 2007) and neurocomputational analyses (Bastos et al.”

“With high glucocorticoid concentrations, postsynaptic dendritic spines are lost and dendritic branches shrink in various parts of the cortex and the hippocampus (Dias-Ferreira et al., 2009; Liston and Gan, 2011; Liston et al., 2006; Radley et al., 2006; Watanabe et al., 1992; Wellman, 2001).”

“1; two asterisks) (McEwen, 2012).”

“In dendritic spine remodeling, learning leads to the induction of spine formation, and successively, a portion of novel spines is stabilized and a portion of existing spines is pruned (Hubener and Bonhoeffer, 2010; Yang et al., 2009).”

“Beliefs about the current states of the world/body, about the attainable states, and about the goal states are proposed to be represented in the lateral PFC, the pre-SMA and the vmPFC/OFC, respectively.”

“In summary, NE ignites hotspots at neurotransmitter release sites, thus increasing the transmitted information (bits per second). demonstrated that neurons take up energy ‘on demand’ (Magistretti et al., 1999; Pellerin and Magistretti, 1994).”

“The ‘states that agents believe they should occupy’ are represented in regions like the ventromedial prefrontal cortex prefrontal cortex (vmPFC) and the orbitofrontal cortex (OFC) (Barron et al., 2015; Bechara et al., 2000; Gottfried et al., 2003; O'Doherty et al., 2003; Roesch and Olson, 2004).”

“Another example concerns the allostatic (predictive) regulation of the internal body milieu (Sterling, 2012), where viscerosensory prediction errors are reduced (Barrett and Simmons, 2015).”

“The ‘visceromotor regions’ controlling the allostatic processes (the amygdala, ventral striatum, insula, orbitofrontal cortex, anterior cingulate cortex, medial prefrontal cortex) are commonly regarded as the ‘circuits for emotions’ (Barrett, 2017).”

“2) (Nguyen et al., 2014; Rushworth et al., 2004).”

“This number is larger than 6 for cortical pyramidal to interneuron synapses, larger than 4 for pyramidal cell to pyramidal cell synapses in cortex, and 6 for excitatory synapses onto pyramidal cells in hippocampal area CA1 (Deuchars and Thomson, 1995; Larkman et al., 1997; Markram et al., 1997).”

“From the physical point of view, the following applies: Obtaining any information costs energy, erasing information produces energy (Berut et al., 2012; Brillouin, 1953; Toyabe et al., 2014; Tribus and McIrvine, 1972).”

“SNS and HPA-axis activations immediately suppress insulin secretion from the pancreatic b-cells (Ahren, 2000; Chan et al., 2007; Frühwald-Schultes et al., 2000; Tong et al., 2007).”

“He emphasized that novelty, unpredictability, and uncontrollability of a condition and expectation of adverse sequels are key triggers of a stress reaction (Mason,1968).”

“With high glucocorticoid concentrations, postsynaptic dendritic spines are lost and dendritic branches shrink in various parts of the cortex and the hippocampus (Dias-Ferreira et al., 2009; Liston and Gan, 2011; Liston et al., 2006; Radley et al., 2006; Watanabe et al., 1992; Wellman, 2001).”

“3) (Swanson, 2000).”

“With high glucocorticoid concentrations, postsynaptic dendritic spines are lost and dendritic branches shrink in various parts of the cortex and the hippocampus (Dias-Ferreira et al., 2009; Liston and Gan, 2011; Liston et al., 2006; Radley et al., 2006; Watanabe et al., 1992; Wellman, 2001).”

“Over the past forty years, many researchers have defined stressful situations – from a bio-psychological perspective – as characterized by ‘no information, no control, uncertainty with a sense of threat’ (Koolhaas et al., 2011; Lyons and Levine, 1994; Monat et al., 1972).”

“For example, motor reflexes can be described as quenching proprioceptive prediction errors (Adams et al., 2013).”

“…Na+ action potentials interact with the weak distal synaptic input; such an interaction generates forward propagated Ca++ action potentials that in turn elicit a burst of multiple action potentials originating from the axonal spike initiation zone (Larkum, 2013; Larkum et al., 2004).”

“The same notion of minimizing expected prediction errors in the future (i.e., uncertainty) underlies extension of active inference into the domain of goal-directed-decision making and planning (Friston et al., 2015).”

“Cortisol passes the blood-brain-barrier easily and binds to mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) located in and on neurons of the hippocampus, the amygdala, and the cerebral cortex (Arriza et al., 1988; McEwen et al., 1968; Patel et al., 2000; Sanchez et al., 2000).”

“But neurons can also can sum up their inputs to elicit an action potential (Konig et al., 1996; Shadlen and Newsome, 1994).”

“With respect to synaptic plasticity; i.e., long-term potentiation (LTP) and long-term depression (LTD), MR and GR have been shown to act in an opposing manner on gene expression (Diamond et al., 1992; Pavlides et al., 1994, 1996).”

“These people show only low stress responses and intermediate levels of self-esteem and locus of control (Kirschbaum et al., 1995; Pruessner et al., 2005, 1999).”

“5)(Ramos and Arnsten, 2007).”

“Neuroanatomically, the notion of a hierarchy is based on the distinction between bottom-up and top-down connections (Salin and Bullier, 1995).”

“The ACC-amygdala complex can stimulate two important descending projections: first, the pathway to the locus coeruleus (LC); this activation causes a hypervigilant state (Hermans et al., 2011; Reyes et al., 2011; Valentino and Van Bockstaele, 2008), which has been linked to an augmented brain energy consumption (Hitze…”

“The ‘states that agents believe they should occupy’ are represented in regions like the ventromedial prefrontal cortex prefrontal cortex (vmPFC) and the orbitofrontal cortex (OFC) (Barron et al., 2015; Bechara et al., 2000; Gottfried et al., 2003; O'Doherty et al., 2003; Roesch and Olson, 2004).”

“With high glucocorticoid concentrations, postsynaptic dendritic spines are lost and dendritic branches shrink in various parts of the cortex and the hippocampus (Dias-Ferreira et al., 2009; Liston and Gan, 2011; Liston et al., 2006; Radley et al., 2006; Watanabe et al., 1992; Wellman, 2001).”

“However, if we are uncertain about whether we might get food at all, stress occurs – as is the case in ‘food insecurity’ (Bhattacharya et al., 2004).”

“In fact, there is experimental evidence supporting the view that habituation has all the hallmarks of predictive coding (Ramaswami, 2014; Wacongne et al., 2012).”

“The ‘states that agents believe they should occupy’ are represented in regions like the ventromedial prefrontal cortex prefrontal cortex (vmPFC) and the orbitofrontal cortex (OFC) (Barron et al., 2015; Bechara et al., 2000; Gottfried et al., 2003; O'Doherty et al., 2003; Roesch and Olson, 2004).”

“, normal) levels cause translocation of glucocorticoid receptors into mitochondria to promote Ca++ sequestration and maintain low levels of free radicals (Du et al., 2009).”

“According to the calculations of Levy and Baxter, such a high glutamate release probability – that is induced by high LC activation – is energetically much more expensive than synaptic transmission occurring with low LC activation, which constitutes the economically optimal mode (Levy and Baxter, 1996).”

“In agreement with neuroanatomical studies (Feldmeyer et al., 2005; Harris and Shepherd, 2015; Lubke et al., 2000; Ramaswamy and Markram, 2015; Thomson and Lamy, 2007) and neurocomputational analyses (Bastos et al.”

“Cortisol passes the blood-brain-barrier easily and binds to mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) located in and on neurons of the hippocampus, the amygdala, and the cerebral cortex (Arriza et al., 1988; McEwen et al., 1968; Patel et al., 2000; Sanchez et al., 2000).”

“7C) (Diamond et al., 1992; Joels, 2006; Pavlides et al., 1994, 1996).”

“SNS and HPA-axis activations immediately suppress insulin secretion from the pancreatic b-cells (Ahren, 2000; Chan et al., 2007; Frühwald-Schultes et al., 2000; Tong et al., 2007).”

“004 behaviors lead to inefficient mitochondrial metabolism, resulting in reactive oxygen species (ROS) and inflammation and worsen systemic and brain pathology (Picard et al., 2014).”

“Here, we focus on how declarative memories are formed under stress, which is distinct from the way emotional memories are conserved (Maggio and Segal, 2012; Quirarte et al., 1997; Zhou et al., 2010).”

“The amygdala (by exchanging information with the orbitofrontal cortex) may play a key role in responding to threats to wellbeing (Schulkin et al., 1994).”

“From the physical point of view, the following applies: Obtaining any information costs energy, erasing information produces energy (Berut et al., 2012; Brillouin, 1953; Toyabe et al., 2014; Tribus and McIrvine, 1972).”

“Therefore, high glucocorticoid concentrations may lead to ‘unlearning’ of the precision of prediction errors, while low concentrations of glucocorticoids may facilitate the learning of precision weighting (Liston et al., 2013; Liston and Gan, 2011).”

“Stress habituation can be viewed as a special form of learning, in which not only the glucocorticoids, but also the endocannabinoids play a central role (Hill et al., 2010; Patel and Hillard, 2008).”

“Randomized controlled trials have shown that psychosocial stress is a factor that causes cardiovascular mortality, and that decreasing allostatic load through stress-relief programs reduces cortisol responses and cardiovascular mortality (Gaab et al., 2003; Gulliksson et al., 2011; Hammerfald et al., 2006; Orth-Gomer…”

“Recently, goal-directed-decision making has been considered in terms of active inference (Friston et al., 2013, 2014).”

“…et al., 2000; Ramaswamy and Markram, 2015; Thomson and Lamy, 2007) and neurocomputational analyses (Bastos et al., 2012; Haeusler and Maass, 2007; Shipp, 2016; Shipp et al., 2013), we propose the following assignment of empirical prior beliefs, the likelihood, the sensory data, and the…”

“These people show only low stress responses and intermediate levels of self-esteem and locus of control (Kirschbaum et al., 1995; Pruessner et al., 2005, 1999).”

“When animals recovered from stress, distal dendrites were not fully rebuilt, but proximal dendrites showed hyperextension and spine growth, and deficits in synaptic plasticity were complete restored (Goldwater et al., 2009).”

“Moreover, the better people tune their beliefs about uncertainty, the better they were able to predict future outcomes – suggesting that the stress response has an adaptive function (de Berker et al., 2016).”

“Randomized controlled trials have shown that psychosocial stress is a factor that causes cardiovascular mortality, and that decreasing allostatic load through stress-relief programs reduces cortisol responses and cardiovascular mortality (Gaab et al., 2003; Gulliksson et al., 2011; Hammerfald et al., 2006; Orth-Gomer…”

“In agreement with neuroanatomical studies (Feldmeyer et al., 2005; Harris and Shepherd, 2015; Lubke et al., 2000; Ramaswamy and Markram, 2015; Thomson and Lamy, 2007) and neurocomputational analyses (Bastos et al., 2012; Haeusler and Maass, 2007; Shipp, 2016; Shipp et al., 2013), we propose the…”

“Experimental evidence supports the notion that the principles of active inference underlie the functioning of the visual and auditory systems (Chennu et al., 2013; Kok and de Lange, 2014).”

“The notion of top-down connections provided a better explanation of experimental data than the idea that only bottom-up connections are necessary (Garrido et al., 2007).”

“Recently, goal-directed-decision making has been considered in terms of active inference (Friston et al., 2013, 2014).”

“While sleep normally serves to optimize and conserve our generative models (Hobson and Friston, 2012), poor sleep is likely to preclude the revision of inappropriate models (Wagner and Born, 2008).”

“Beliefs about the current states of the world/body, about the attainable states, and about the goal states are proposed to be represented in the lateral PFC, the pre-SMA and the vmPFC/OFC, respectively.”

“Remarkably, an experimental mental or psychosocial challenge increases whole-brainglucose uptake by more than 10% (Hitze et al., 2010; Madsen et al., 1995).”

“pain, cutaneous light ‘sensual’ touch and thermal sensations) that result from changes in the internal body milieu (viscera, muscles and skin) (Barrett and Simmons, 2015; Chanes and Barrett, 2016).”

“…stress-related responses are broadcast by the ACC to the anterior insular and onto autonomic centers to elicit autonomic reflexes (Barrett and Simmons, 2015; Behrens et al., 2007; Feinstein et al., 2006; Karlsson et al., 2012; Liljeholm et al., 2013; Paulus et al., 2002; Sarinopoulos et al., 2010).”

“Cortisol passes the blood-brain-barrier easily and binds to mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) located in and on neurons of the hippocampus, the amygdala, and the cerebral cortex (Arriza et al., 1988; McEwen et al., 1968; Patel et al., 2000; Sanchez et al., 2000).”

“Basolateral amygdala neurons expand dendrites from chronic stress (Chattarji et al., 2015) while, as noted earlier, medial PFC neurons, as well as hippocampal neurons, show dendritic shrinkage from the same stress (McEwen and Morrison, 2013).”

“…stress-related responses are broadcast by the ACC to the anterior insular and onto autonomic centers to elicit autonomic reflexes (Barrett and Simmons, 2015; Behrens et al., 2007; Feinstein et al., 2006; Karlsson et al., 2012; Liljeholm et al., 2013; Paulus et al., 2002; Sarinopoulos et al., 2010).”

“With respect to synaptic plasticity; i.e., long-term potentiation (LTP) and long-term depression (LTD), MR and GR have been shown to act in an opposing manner on gene expression (Diamond et al., 1992; Pavlides et al., 1994, 1996).”

“, 2000; Ramaswamy and Markram, 2015; Thomson and Lamy, 2007) and neurocomputational analyses (Bastos et al., 2012; Haeusler and Maass, 2007; Shipp, 2016; Shipp et al., 2013), we propose the following assignment of empirical prior beliefs, the likelihood, the sensory data, and the prediction errors to their anatomical…”

“In all other cases, LTP is attenuated or even LTD occurs (Maggio and Segal, 2007, 2009).”

“Due to the opposing actions of MR and GR, the difference in effects on gene expression becomes paramount (Datson et al., 2001).”

“, 2000; Ramaswamy and Markram, 2015; Thomson and Lamy, 2007) and neurocomputational analyses (Bastos et al., 2012; Haeusler and Maass, 2007; Shipp, 2016; Shipp et al., 2013), we propose the following assignment of empirical prior beliefs, the likelihood, the sensory data, and the prediction errors to their anatomical…”

“High glucocorticoid concentrations have been shown to favor postsynaptic dendritic spine formation (GRs exert trophic effects via TrkB signaling) (Ikeda et al., 2015; Jeanneteau et al., 2008), whereas low glucocorticoid concentrations are required for the stabilization of freshly formed spines, the latter process bein…”

“The degree of uncertainty about what to do next . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Abbreviations: ACC, anterior cingulate cortex; GABA, g-aminobutyric acid; GLUT1, glucose transporter 1; GLUT4, glucose transporter 4; GR, glucocorti…”

“…energy’ (in bits) and ‘thermodynamic energy’ (in Joules) closely coupled, a finding that emerged first when analyzing their interrelation mathematically (Sengupta et al., 2013, 2016), and second when studying experimentally how the brain responds to stress (Harris et al., 2012; Hitze et al., 2010).”

“These people show only low stress responses and intermediate levels of self-esteem and locus of control (Kirschbaum et al., 1995; Pruessner et al., 2005, 1999).”

“In agreement with neuroanatomical studies (Feldmeyer et al., 2005; Harris and Shepherd, 2015; Lubke et al., 2000; Ramaswamy and Markram, 2015; Thomson and Lamy, 2007) and neurocomputational analyses (Bastos et al.”

“Plasticity and remodeling are processes that consume a considerable amount of energy (Placais and Preat, 2013).”

“In fact, there is experimental evidence supporting the view that habituation has all the hallmarks of predictive coding (Ramaswami, 2014; Wacongne et al., 2012).”

“Consequently, insulin-dependent GLUT4mediated glucose uptake in muscle and fat is prevented, rebalancing energy consumption in favor of the insulin-independent GLUT1-mediated glucose uptake at the blood-brain barrier (Hasselbalch et al., 1999).”

“Such a prioritization of brain energy metabolism is an inherent feature in vertebrates – a feature that is evident on short and long time-scales for preserving cerebral function, energy and mass during stress or food deprivation (Gong et al., 1998; Kind et al., 2005; Miller et al., 2002; Muhlau et al., 2007).”

“Stress habituation can be viewed as a special form of learning, in which not only the glucocorticoids, but also the endocannabinoids play a central role (Hill et al., 2010; Patel and Hillard, 2008).”

“The concept of NE hot spots (Mather et al., 2015) nicely explains two experimental observations: First, increasing the frequency of LC stimulation either leads to facilitation or suppression of sensory evoked neuronal responses (Devilbiss and Waterhouse, 2004).”

“Randomized controlled trials have shown that psychosocial stress is a factor that causes cardiovascular mortality, and that decreasing allostatic load through stress-relief programs reduces cortisol responses and cardiovascular mortality (Gaab et al., 2003; Gulliksson et al., 2011; Hammerfald et al., 2006; Orth-Gomer…”

“In agreement with neuroanatomical studies (Feldmeyer et al., 2005; Harris and Shepherd, 2015; Lubke et al., 2000; Ramaswamy and Markram, 2015; Thomson and Lamy, 2007) and neurocomputational analyses (Bastos et al.”

“…stress-related responses are broadcast by the ACC to the anterior insular and onto autonomic centers to elicit autonomic reflexes (Barrett and Simmons, 2015; Behrens et al., 2007; Feinstein et al., 2006; Karlsson et al., 2012; Liljeholm et al., 2013; Paulus et al., 2002; Sarinopoulos et al., 2010).”

“It works like this: Decreased glucocorticoid concentrations stimulate the HPA-axis, while increased glucocorticoid concentrations (circadian or stress-induced) inhibit it (Akana et al., 1988; Fehm et al., 1977; Jacobson et al., 1988; Peters idal neuron is involved in precision control.”

“Likewise, inappropriate updates can lead to disturbed sleep or bad dreams (Antonijevic, 2008; Rodenbeck and Hajak, 2001).”

“As a consequence of an alleviated allostatic load, habituators can tolerate an inhospitable environment and are sheltered against cerebro- and cardiovascular events (Carroll et al., 2012; Everson et al., 1997; Hamer et al., 2010; Lynch et al., 1998; Seldenrijk et al., 2012).”

“…energy’ (in bits) and ‘thermodynamic energy’ (in Joules) closely coupled, a finding that emerged first when analyzing their interrelation mathematically (Sengupta et al., 2013, 2016), and second when studying experimentally how the brain responds to stress (Harris et al., 2012; Hitze et al., 2010).”

“Here, cortisol regulates synaptic plasticity (long-term potentiation and long-term depression) and in this way gates learning (Maggio and Segal, 2007, 2009; Pavlides et al., 1995).”

“It has been shown experimentally that three input paths can influence the output of the pyramidal cell: driving input, excitatory modulation input and inhibitory modulation input (Mehaffey et al., 2005; Silver, 2010).”

“In contrast, consolidation is unlikely when glucocorticoids are absent (left-hand side of the bell-shaped curve) (Wagner et al., 2005) or when glucocorticoid concentrations are high (right-hand side of the bell-shaped curve) (Plihal et al., 1999).”

“In all other cases, LTP is attenuated or even LTD occurs (Maggio and Segal, 2007, 2009).”

“While sleep normally serves to optimize and conserve our generative models (Hobson and Friston, 2012), poor sleep is likely to preclude the revision of inappropriate models (Wagner and Born, 2008).”

“, 2013, 2016), and second when studying experimentally how the brain responds to stress (Harris et al., 2012; Hitze et al., 2010).”

“According to the concept of ‘allostatic load’ – developed by one of us (McEwen and Stellar, 1993) – the neuroendocrine, cardiovascular, neuroenergetic, and emotional responses become persistently”

“Evidence accumulated that learning is suspended when glucocorticoids are persistently secreted during chronic stress (Bangasser and Shors, 2007; De Quervain et al., 1998; Lupien et al., 1998).”

“2) (Nguyen et al., 2014; Rushworth et al., 2004).”

“retrieval is optimal at low (normal range) glucocorticoid concentrations, but impaired at very low and very high glucocorticoid concentrations (Rimmele et al., 2013).”

“Thus, a setpoint is generated that depends primarily on the functioning of the MR in coordination with GR (de Kloet et al., 1998; Peters et al., 2007a).”

“Acute and chronic stress interferes with cognition, decision making, anxiety and mood, and in so doing affects systemic physiology through neuroendocrine, autonomic, immune and metabolic mediators and multi-morbidity of disorders frequently occurs (McEwen, 2007; McEwen et al., 2015b; Rasgon and McEwen, 2016).”

“In contrast, consolidation is unlikely when glucocorticoids are absent (left-hand side of the bell-shaped curve) (Wagner et al., 2005) or when glucocorticoid concentrations are high (right-hand side of the bell-shaped curve) (Plihal et al., 1999).”

“…stress-related responses are broadcast by the ACC to the anterior insular and onto autonomic centers to elicit autonomic reflexes (Barrett and Simmons, 2015; Behrens et al., 2007; Feinstein et al., 2006; Karlsson et al., 2012; Liljeholm et al., 2013; Paulus et al., 2002; Sarinopoulos et al., 2010).”

“Such a prioritization of brain energy metabolism is an inherent feature in vertebrates – a feature that is evident on short and long time-scales for preserving cerebral function, energy and mass during stress or food deprivation (Gong et al., 1998; Kind et al., 2005; Miller et al., 2002; Muhlau et al., 2007).”

“This number is larger than 6 for cortical pyramidal to interneuron synapses, larger than 4 for pyramidal cell to pyramidal cell synapses in cortex, and 6 for excitatory synapses onto pyramidal cells in hippocampal area CA1 (Deuchars and Thomson, 1995; Larkman et al., 1997; Markram et al., 1997).”

“The ACC-amygdala complex can stimulate two important descending projections: first, the pathway to the locus coeruleus (LC); this activation causes a hypervigilant state (Hermans et al., 2011; Reyes et al., 2011; Valentino and Van Bockstaele, 2008), which has been linked to an augmented brain energy consumption (Hitze…”

“Here, we focus on how declarative memories are formed under stress, which is distinct from the way emotional memories are conserved (Maggio and Segal, 2012; Quirarte et al., 1997; Zhou et al., 2010).”

“It works like this: Decreased glucocorticoid concentrations stimulate the HPA-axis, while increased glucocorticoid concentrations (circadian or stress-induced) inhibit it (Akana et al., 1988; Fehm et al., 1977; Jacobson et al., 1988; Peters idal neuron is involved in precision control.”

“SNS and HPA-axis activations immediately suppress insulin secretion from the pancreatic b-cells (Ahren, 2000; Chan et al., 2007; Frühwald-Schultes et al., 2000; Tong et al., 2007).”

“With respect to synaptic plasticity; i.e., long-term potentiation (LTP) and long-term depression (LTD), MR and GR have been shown to act in an opposing manner on gene expression (Diamond et al., 1992; Pavlides et al., 1994, 1996).”

“Randomized controlled trials have shown that psychosocial stress is a factor that causes cardiovascular mortality, and that decreasing allostatic load through stress-relief programs reduces cortisol responses and cardiovascular mortality (Gaab et al., 2003; Gulliksson et al., 2011; Hammerfald et al., 2006; Orth-Gomer…”

“Such a prioritization of brain energy metabolism is an inherent feature in vertebrates – a feature that is evident on short and long time-scales for preserving cerebral function, energy and mass during stress or food deprivation (Gong et al., 1998; Kind et al., 2005; Miller et al., 2002; Muhlau et al., 2007).”

“Furthermore, at low NE concentrations the actions of high-affine a2-adrenoreceptors prevail, while at high NE concentrations the actions of low-affine a1and b-adrenoreceptors prevail (Nai et al., 2009, 2010).”

“Such a prioritization of brain energy metabolism is an inherent feature in vertebrates – a feature that is evident on short and long time-scales for preserving cerebral function, energy and mass during stress or food deprivation (Gong et al., 1998; Kind et al., 2005; Miller et al., 2002; Muhlau et al., 2007).”

“NE enhances GABA-release probabilities by low-affine a1adrenoreceptors, whereas NE suppresses GABA-release probabilities by high-affine a2-adrenoreceptors (Hirono and Obata, 2006; Salgado et al., 2012).”

“, 2008), such increases in SNS and HPA-axis activity are common in everyday life (Peters and Langemann, 2009).”

“Here, we focus on how declarative memories are formed under stress, which is distinct from the way emotional memories are conserved (Maggio and Segal, 2012; Quirarte et al., 1997; Zhou et al., 2010).”

“It works like this: Decreased glucocorticoid concentrations stimulate the HPA-axis, while increased glucocorticoid concentrations (circadian or stress-induced) inhibit it (Akana et al., 1988; Fehm et al., 1977; Jacobson et al., 1988; Peters idal neuron is involved in precision control.”

“This number is larger than 6 for cortical pyramidal to interneuron synapses, larger than 4 for pyramidal cell to pyramidal cell synapses in cortex, and 6 for excitatory synapses onto pyramidal cells in hippocampal area CA1 (Deuchars and Thomson, 1995; Larkman et al., 1997; Markram et al., 1997).”

“Noteworthy, NE also affects postsynaptic excitability of cortical neurons (by suppressing excitatory and inhibitory postsynaptic potentials) (Kobayashi et al., 2009; Salgado et al., 2011), but the facilitatory NE effects on presynaptic neurotransmitter release (glutamate and GABA) have been shown to override the less…”

“Furthermore, at low NE concentrations the actions of high-affine a2-adrenoreceptors prevail, while at high NE concentrations the actions of low-affine a1and b-adrenoreceptors prevail (Nai et al., 2009, 2010).”

“High glucocorticoid concentrations have been shown to favor postsynaptic dendritic spine formation (GRs exert trophic effects via TrkB signaling) (Ikeda et al., 2015; Jeanneteau et al., 2008), whereas low glucocorticoid concentrations are required for the stabilization of freshly formed spines, the latter process bein…”

“While low-affine a1- and b-adrenoreceptors increase the glutamate release probability (Ferrero et al., 2013; Kobayashi et al., 2009), high-affine a2-adrenoreceptors receptors decrease it (Chiu et al., 2011).”

“Thus, a setpoint is generated that depends primarily on the functioning of the MR in coordination with GR (de Kloet et al., 1998; Peters et al., 2007a).”

“While low-affine a1- and b-adrenoreceptors increase the glutamate release probability (Ferrero et al., 2013; Kobayashi et al., 2009), high-affine a2-adrenoreceptors receptors decrease it (Chiu et al.”

“As a consequence of an alleviated allostatic load, habituators can tolerate an inhospitable environment and are sheltered against cerebro- and cardiovascular events (Carroll et al., 2012; Everson et al., 1997; Hamer et al., 2010; Lynch et al., 1998; Seldenrijk et al., 2012).”

“As stress-induced tachycardia increases flow velocity in the arterial vascular system, high flow speed in turn increases the risk of arterial turbulences (Falsetti et al., 1983) – particularly at branching sites of the blood vessel system (Malek et al.”

“NE enhances GABA-release probabilities by low-affine a1adrenoreceptors, whereas NE suppresses GABA-release probabilities by high-affine a2-adrenoreceptors (Hirono and Obata, 2006; Salgado et al., 2012).”

“In this respect, the brain behaves ‘selfishly’ – as has been confirmed experimentally (Hitze et al., 2010; Kubera et al., 2012b; Oltmanns et al., 2008; Peters et al., 2011).”

“While low-affine a1- and b-adrenoreceptors increase the glutamate release probability (Ferrero et al., 2013; Kobayashi et al., 2009), high-affine a2-adrenoreceptors receptors decrease it (Chiu et al., 2011).”

“…(Carhart-Harris, 2018a), exemplified by findings of increased brain complexity/entropy (Schartner et al., 2017) and decreased modular differentiation (Petri et al., 2014), provides an iconic image of dysregulated global brain function under psychedelics, with the 5-HT2AR as the trigger point.”

“There is now a wealth of research in adults demonstrating that individual variability in neurobiological responses to stress is informed through the assessment of factors that shape perceptions and interpretations of stress [10, 179, 180].”

“This extended activation alters brain architecture in regions such as the PFC, amygdala, and hippocampus, which undermines adaptive regulation and coping (Peters et al., 2017).”

“…attentional bias toward threat (Hakamata et al. 2010), increased worry and self-related cognitions, dysfunctional learning about bodily states over time (Van den Bergh et al. 2017), and increased allostatic load leading to increased stress and mental illness (Peters et al. 2017, Sterling 2014).”

“…Castelfranchi, 2009; Stepp, 2009; Shemesh et al., 2010; Stepp and Turvey, 2010; Mossbridge et al., 2012; Dhar et al., 2013; Goel and Mehta, 2013; Bohm et al., 2016; De Berker et al., 2016; Katz and Springer, 2016; Peters et al., 2017; Wilson et al., 2017; Gagliano et al., 2018; Katz et al., 2018).”